This application addresses broad Challenge Area (08) Genomics and Specific Challenge Topic, 08-HL-101* "Identify causal genetic variants associated with heart, lung, and blood diseases by application of targeted DNA capture and massively parallel sequencing technologies followed by selective genotyping of DNA samples from large well-phenotyped populations". Idiopathic Pulmonary fibrosis (IPF) is a progressive untreatable lung disease. IPF has eluded causal genetic determinants that may provide targets for novel therapeutic approaches. The objective of this proposed research is to identify causal genetic variants contributing to risk of IPF using a Genome-wide association studies (GWAS) panel in a large complied cohort. Each DNA sample is accompanied by detailed phenotypic data. To meet this objective we have the following specific aims: Specific Aim 1. To establish a combined cohort of over 700 IPF patients and perform a Genome Wide Association Study (GWAS) in 450 subjects with IPF. The hypothesis to be tested is that inheritable genetic factors affect individual susceptibility of IPF. To accomplish this we will establish clinically meaningful definitions for disease phenotypes in a merged manually and electronically curated database of all 700 collaborator patient sample sets of IPF patients and then perform a complete a GWAS using Affymetrix SNP 6.0 GeneChip(R) in 450 IPF patients and deposit the GWAS genotype and phenotype data in the NIH repository in dbGap. Specific Aim 2. Conduct both standard and novel analyses in genetic variation by phenotypes severity and rapidity of progression. The hypothesis to be tested is that inheritable genetic factors influence prognosis and severity of the disease. To accomplish this we will determine SNPs associated with IPF utilizing publicly deposited genotyped control GWAS data and evaluate copy number polymorphisms via available probes, and test for association with IPF phenotypes and determine if the associated variants differ in frequency between subjects with "rapidly progressive" IPF with high mortality versus those with "slow" IPF, severity grade or other clinical outcome measures Specific Aim 3. Perform Exon-Wide targeted DNA sequencing and genotyping to validate the GWAS associated genetic variants and to discover functional variations in Caucasians and African Americans with IPF. The hypothesis to be tested is that Exon-Wide sequencing of subjects with different ethnic and racial backgrounds and severity cohorts will allow the identification of causal/functional variants associated with IPF. We will replicate the most significant associations with a selective SNP array in a replicate IPF patient cohort of 200 subjects and then perform Exon-wide sequencing of 48 genes in 160 Caucasian and African American subjects using Illumina 454 technology and conduct a statistical analysis of exon variants discovered in sub- aim b. We expect that completion of a genome-wide association study using clinically meaningful phenotypes coupled to exon-wide re-sequencing will lead to identification of the genes and the specific genetic variants that contribute to the development of IPF. This can then be used as guide to lead to new approaches for preventing and treating this deadly disease.